This invention relates to an apparatus and method for monitoring the cardiac function of heart transplant patients for the purpose of detecting cardiac allograft rejection, and more particularly to an apparatus and method for detecting cardiac allograft rejection and responding to such detection by providing a warning signal to the patient or by controlling the output of an implanted infusion pump adapted to administer anti-rejection drugs.
Cardiac transplantation is an accepted therapy for end stage cardiac disease. After transplantation, cardiac allograft rejection by the patient's immune system is a serious and life-long problem requiring intensive medical therapy and close follow-up. In the early years of cardiac transplantation, immunosuppressing drugs such as azathioprine and steroids were used to treat heart rejection problems. To determine when to administer these drugs and the proper dosage, physicians would perform periodic endomyocardial biopsy operations.
Typically a cardiac transplant patient undergoes an endomyocardial biopsy once per week immediately after transplantation and less frequently thereafter. An average patient will have twelve biopsies in the first year after transplantation. The biopsy schedule increases if the physician suspects rejection.
To perform a cardiac biopsy operation, the physician introduces a large catheter into the body through the femoral or jugular vein. The operation is uncomfortable and inconvenient for the patient, potential complications are infection, arrhythmias, heart block, and cardiac perforation. Biopsy is an invasive operation; therefore some recovery time must transpire between operations. In the interim period, rejection may begin or worsen without detection. In addition, the physician must presume, possibly incorrectly, that a limited sample of tissue reflects the histology of the heart as a whole.
An alternative method to monitor and detect rejection is highly desirable to avoid the need for repeated invasive endomyocardial biopsy procedures. The first attempts to develop such an alternative employed standard body surface electrocardiogram sensing techniques wherein physicians would analyze the cardiac electrical signals of natural (not stimulated) heartbeats. A gradual decrease in the electrocardiogram amplitude over a period of a few days showed some correlation with heart rejection. Unfortunately, this manner of diagnosis has proven inaccurate in a high percentage of studies, often giving widely variable results from patient to patient and even from one study to the next in the same patient. Further reducing the diagnostic value of body surface electrocardiogram analysis is the fact that the amplitude reduction appears only late in the course of rejection, if it even appears in a diagnostic manner.
A report by A. Keren et al., entitled "Heart Rejection Transplant Monitoring by Signal-averaged Electrocardiography in Patients Receiving Cyclosporine", CIRCULATION, Vol. 70, pages 1-124 (1984), indicates that some improvement in the diagnostic utility of body surface electrocardiogram analysis has been achieved by using signal-averaging techniques. But even these techniques have proven inadequate for detecting rejection shortly after the transplant operation or for detecting mild rejection some time after the transplant operation. Other researchers have improved body surface sensing and analysis results by performing frequency analysis of the electrocardiogram. See, for example, the report by R. Haberl et al., entitled "Frequency Analysis of the Surface Electrogram for Recognition of Acute Rejection After Orthotopic Cardiac Transplantation in Man", CIRCULATION, Vol. 76, page 101 (1987). Frequency analysis shows that changes in spectral morphology, rather than QRS amplitude, offers improved correlation with rejection. To date, none of the body surface electrogram sensing techniques has shown sufficient sensitivity and specificity to replace the biopsy for the detection of rejection.
Since the time of the first application of body surface electrocardiogram sensing techniques to the problem of rejection prediction, cyclosporine became available for usage as an immunosuppressive agent. Cyclosporine led to the improved survival among transplant recipients as well as an increase in the use of transplantation as a treatment for severe cardiac disease. Immunosuppression treatment using cyclosporine is an improvement over treatment with azathioprine and steroids because it is associated with less myocardiac edema. Unfortunately, reduced myocardiac edema lessens the signs of rejection on the standard external electrocardiogram. Because cyclosporine treatment has further diminished the diagnostic efficacy of external electrocardiograms, endomyocardial biopsy is now the only reliable method for detecting rejection in the transplanted heart.
The intrinsic intracardiac electrogram, measured from leads implanted within the heart, is another type of cardiac electrical signal previously evaluated to detect allograft rejection. See, for example, the report by H. Warnecke et al., entitled "Noninvasive Monitoring of Cardiac Allograph Rejection by Intramyocardial Electrogram Recordings", CIRCULATION, Vol. 74, page III-72 (1986). Although intracardiac electrogram monitoring requires the implantation of a sensing electrode and a signal detecting and transmitting device, rendering the procedure technically invasive, following implantation the device sends signals to an external communicating device in a non-invasive manner.